Cerebral cavernous malformations (CCMs) are congenital vascular abnormalities of the central nervous system that can result in stroke, seizures, and focal neurologic deficits. Familial forms of CCM are inherited in an autosomal dominant fashion, with three known loci. The CCM1 gene is Kritl, the CCM2 is MGC4607, and the CCM3 gene has not yet been identified. The identification of the CCM3 gene is the focus of this proposal, and the following specific aims will be addressed: 1) reduce the size of the CCM3 critical interval through recombination analysis; 2) screen candidate genes for mutations in affected individuals; and 3) identify binding partners of the CCM2 protein through a yeast two-hybrid assay and use the results to help select CCM3 candidates. The identification of the causative gene for CCM3 is critical, not only for improved diagnostics of individuals with a family history of CCMs, but also to help further elucidate the pathogenesis of CCMs. The CCM proteins are part of a complex pathway that, when perturbed through the loss of one member, causes abnormal vascular morphogenesis in the brain leading to CCM formation. Understanding the CCM pathway will also provide important data to better understand stroke and seizure.